Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles

Simone M Crivelli; Caterina Giovagnoni; Zhihui Zhu; Priyanka Tripathi; Ahmed Elsherbini; Zainuddin Quadri; Jian Pu; Liping Zhang; Branislav Ferko; Dusan Berkes; Stefka D Spassieva; Pilar Martinez-Martinez; Erhard Bieberich

doi:10.1002/jev2.12233

Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles

Simone M Crivelli, Caterina Giovagnoni, Zhihui Zhu, Priyanka Tripathi, Ahmed Elsherbini, Zainuddin Quadri, Jian Pu, Liping Zhang, Branislav Ferko, Dusan Berkes, Stefka D Spassieva, Pilar Martinez-Martinez^*, Erhard Bieberich^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non-vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT-I). Inhibition of ceramide biosynthesis reduces CERT-Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT-dependent pathway.

Original language	English
Article number	e12233
Number of pages	22
Journal	Journal of Extracellular Vesicles
Volume	11
Issue number	6
DOIs	https://doi.org/10.1002/jev2.12233
Publication status	Published - Jun 2022

Keywords

Carrier Proteins
Ceramides
Endosomal Sorting Complexes Required for Transport/metabolism
Extracellular Vesicles/metabolism
Protein Serine-Threonine Kinases
Sphingolipids
TRANSPORTER
PI4KIII beta
PI4KIII beta-IN-10
Tsg101
ceramide
AlphaFold2
HPA-12
NC03
INHIBITOR
PI4KII alpha
EFFICIENT
extracellular vesicles
TRAFFICKING
ER-endosome contact sites
PI4P
MICRODOMAINS
IN-VIVO
BIOLOGY
EXOSOMES
sphingomyelin
ENDOPLASMIC-RETICULUM
CERT

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Cite this

Crivelli, S. M., Giovagnoni, C., Zhu, Z., Tripathi, P., Elsherbini, A., Quadri, Z., Pu, J., Zhang, L., Ferko, B., Berkes, D., Spassieva, S. D., Martinez-Martinez, P., & Bieberich, E. (2022). Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles. Journal of Extracellular Vesicles, 11(6), Article e12233. https://doi.org/10.1002/jev2.12233

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title = "Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles",

abstract = "The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non-vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT-I). Inhibition of ceramide biosynthesis reduces CERT-Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT-dependent pathway.",

keywords = "Carrier Proteins, Ceramides, Endosomal Sorting Complexes Required for Transport/metabolism, Extracellular Vesicles/metabolism, Protein Serine-Threonine Kinases, Sphingolipids, TRANSPORTER, PI4KIII beta, PI4KIII beta-IN-10, Tsg101, ceramide, AlphaFold2, HPA-12, NC03, INHIBITOR, PI4KII alpha, EFFICIENT, extracellular vesicles, TRAFFICKING, ER-endosome contact sites, PI4P, MICRODOMAINS, IN-VIVO, BIOLOGY, EXOSOMES, sphingomyelin, ENDOPLASMIC-RETICULUM, CERT",

author = "Crivelli, {Simone M} and Caterina Giovagnoni and Zhihui Zhu and Priyanka Tripathi and Ahmed Elsherbini and Zainuddin Quadri and Jian Pu and Liping Zhang and Branislav Ferko and Dusan Berkes and Spassieva, {Stefka D} and Pilar Martinez-Martinez and Erhard Bieberich",

note = "{\textcopyright} 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.",

year = "2022",

month = jun,

doi = "10.1002/jev2.12233",

language = "English",

volume = "11",

journal = "Journal of Extracellular Vesicles",

issn = "2001-3078",

publisher = "Routledge/Taylor & Francis Group",

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Crivelli, SM, Giovagnoni, C, Zhu, Z, Tripathi, P, Elsherbini, A, Quadri, Z, Pu, J, Zhang, L, Ferko, B, Berkes, D, Spassieva, SD, Martinez-Martinez, P & Bieberich, E 2022, 'Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles', Journal of Extracellular Vesicles, vol. 11, no. 6, e12233. https://doi.org/10.1002/jev2.12233

TY - JOUR

T1 - Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles

AU - Crivelli, Simone M

AU - Giovagnoni, Caterina

AU - Zhu, Zhihui

AU - Tripathi, Priyanka

AU - Elsherbini, Ahmed

AU - Quadri, Zainuddin

AU - Pu, Jian

AU - Zhang, Liping

AU - Ferko, Branislav

AU - Berkes, Dusan

AU - Spassieva, Stefka D

AU - Martinez-Martinez, Pilar

AU - Bieberich, Erhard

PY - 2022/6

Y1 - 2022/6

N2 - The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non-vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT-I). Inhibition of ceramide biosynthesis reduces CERT-Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT-dependent pathway.

AB - The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non-vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT-I). Inhibition of ceramide biosynthesis reduces CERT-Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT-dependent pathway.

KW - Carrier Proteins

KW - Ceramides

KW - Endosomal Sorting Complexes Required for Transport/metabolism

KW - Extracellular Vesicles/metabolism

KW - Protein Serine-Threonine Kinases

KW - Sphingolipids

KW - TRANSPORTER

KW - PI4KIII beta

KW - PI4KIII beta-IN-10

KW - Tsg101

KW - ceramide

KW - AlphaFold2

KW - HPA-12

KW - NC03

KW - INHIBITOR

KW - PI4KII alpha

KW - EFFICIENT

KW - extracellular vesicles

KW - TRAFFICKING

KW - ER-endosome contact sites

KW - PI4P

KW - MICRODOMAINS

KW - IN-VIVO

KW - BIOLOGY

KW - EXOSOMES

KW - sphingomyelin

KW - ENDOPLASMIC-RETICULUM

KW - CERT

U2 - 10.1002/jev2.12233

DO - 10.1002/jev2.12233

M3 - Article

C2 - 35642450

SN - 2001-3078

VL - 11

JO - Journal of Extracellular Vesicles

JF - Journal of Extracellular Vesicles

IS - 6

M1 - e12233

ER -